Down-regulation of cholesterol biosynthesis in sitosterolemia: diminished activities of acetoacetyl-CoA thiolase, 3-hydroxy-3-methylglutaryl-CoA synthase, reductase, squalene synthase, and 7-dehydrocholesterol delta7-reductase in liver and mononuclear leukocytes.
Sitosterolemia is a recessively inherited disorder characterized by abnormally increased plasma and tissue plant sterol concentrations. Patients have markedly reduced whole body cholesterol biosynthesis associated with suppressed hepatic, ileal, and mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme in cholesterol biosynthetic pathway, coupled with significantly increased low density lipoprotein (LDL) receptor expression. To investigate the mechanism of down-regulated cholesterol biosynthesis, we assayed several other key enzymes in the cholesterol biosynthetic pathway including acetoacetyl-CoA thiolase, HMG-CoA synthase, squalene synthase, and 7-dehydrocholesterol delta7-reductase activities in liver and freshly isolated mononuclear leukocytes from four sitosterolemic patients and 19 controls. Hepatic acetoacetyl-CoA thiolase, HMG-CoA synthase, reductase, and squalene synthase activities were significantly decreased (P < 0.05) -39%, -54%, -76%, and -57%, respectively, and 7-dehydrocholesterol delta7-reductase activity tended to be lower (-35%) in the sitosterolemic compared with control subjects. The reduced HMG-CoA synthase, reductase, and squalene synthase activities were also found in mononuclear leukocytes from a sitosterolemic patient. Thus, reduced cholesterol synthesis is caused not only by decreased HMG-CoA reductase but also by the coordinate down-regulation of entire pathway of cholesterol biosynthesis. These results suggest that inadequate cholesterol production in sitosterolemia is due to abnormal down-regulation of early, intermediate, and late enzymes in the cholesterol biosynthetic pathway rather than a single inherited defect in the HMG-CoA reductase gene.
Honda
A
A
Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark 07103, USA.
Salen
G
G
Nguyen
L B
LB
Tint
G S
GS
Batta
A K
AK
Shefer
S
S
D000101:Acetyl-CoA C-Acetyltransferase / Q000172:deficiency; D000328:Adult; D002784:Cholesterol / Q000096:biosynthesis*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000172:deficiency; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000172:deficiency; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000172:deficiency; D007963:Leukocytes, Mononuclear / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D010088:Oxidoreductases / Q000172:deficiency; D044925:Oxidoreductases Acting on CH-CH Group Donors; D012855:Sitosterols / Q000097:blood*
D012855:Sitosterols; C025473:gamma-sitosterol; D002784:Cholesterol; D010088:Oxidoreductases; D006903:Hydroxymethylglutaryl CoA Reductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase; D000101:Acetyl-CoA C-Acetyltransferase; D006904:Hydroxymethylglutaryl-CoA Synthase; D013186:Farnesyl-Diphosphate Farnesyltransferase